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Resistance to the nucleotide analogue cidofovir in HPV(+) cells: a multifactorial process involving UMP/CMP kinase 1

Dimitri Topalis1, Tatiane C Nogueira1, Tim De Schutter1

  • 1Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.

Oncotarget
|January 30, 2016
PubMed

Insights

Cidofovir resistance in human papillomavirus-positive tumors is complex. This study reveals that altered metabolism and transporter expression contribute to cidofovir resistance in HPV(+) cancer cells.

Area of Science:

  • Oncology
  • Virology
  • Pharmacology

Background:

  • Human papillomavirus (HPV) is a key driver of cervical cancer and implicated in head and neck cancers.
  • Currently, no drugs are approved for HPV-related diseases, though cidofovir (CDV) shows antiproliferative effects.

Purpose of the Study:

  • To investigate the mechanisms of cidofovir resistance (CDVR) in HPV-positive (HPV(+)) and HPV-negative (HPV(-)) tumor cell lines.
  • To analyze alterations in CDV metabolism, drug sensitivity, and transporter expression in CDV-resistant cells.

Main Methods:

  • Cultured HPV(+) (SiHaCDV, HeLaCDV) and HPV(-) (HaCaTCDV) cell lines were developed for CDV resistance.
  • Quantified CDV metabolites and assessed sensitivity to chemotherapeutics.
  • Investigated the expression of multidrug-resistance transporters (MRP2, P-gp, BCRP).

Main Results:

  • Impaired UMP/CMPK1 activity led to altered CDV metabolism in HPV(+) cell lines (SiHaCDV, HeLaCDV), but not in HPV(-) (HaCaTCDV).
  • Specific mutations (P64T) or down-regulation of UMP/CMPK1 were observed in SiHaCDV and HeLaCDV, respectively.
  • Altered expression of multidrug-resistance transporters was noted in SiHaCDV and/or HeLaCDV, but not in HaCaTCDV.

Conclusions:

  • CDV resistance in HPV(+) tumor cells is a multifactorial process.
  • Mechanisms include impaired CDV metabolism via UMP/CMPK1 alterations and changes in transporter expression.
  • Findings provide insights into potential therapeutic strategies for HPV-related cancers.
Keywords:
NTP metabolismUMP-CMP kinasecervical carcinomacidofovirhuman papillomavirus

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